The present invention relates generally to methods and devices for drug delivery and analyte extraction, and specifically to medical methods and devices for puncturing the outer layer of living skin and to methods and devices for transdermal drug delivery and analyte extraction.
A number of different methods have been developed to perform transdermal drug delivery and/or analyte extraction, including passive diffusion of a drug or analyte between a skin patch and skin, as well as active processes such as iontophoresis, sonophoresis, electroporation, and chemically enhanced diffusion. These methods are primarily used for generating transdermal movement of small molecules, but generally do not enhance the motion of large molecules through the 10-50 micron thick outermost layer of the skin, the stratum corneum epidermidis.
In an article, xe2x80x9cMicromachined needles for the transdermal delivery of drugs,xe2x80x9d IEEE 11th Annual International Workshop on Micro-Electro-Mechanical Systems (1998), pp. 494-498, which is incorporated herein by reference, Henry et al. discuss a method of mechanically puncturing the skin with microneedles in order to increase the permeability of skin to a test drug. In the article, microfabrication techniques are described to etch an array of needles in silicon, and experiments performed on cadaver skin with the needle array demonstrated an increase in permeability subsequent to puncture of the skin. The needles are created with a predetermined length, and penetrate to the same depth from the skin surface, regardless of the local thickness of the stratum corneum. It is known that if the needles are longer than the local thickness, then the underlying epidermal tissue may be injured, while if the needles are too short, channel formation through the stratum corneum may be incomplete.
U.S. Pat. Nos. 4,775,361, 5,165,418, and 5,423,803, and PCT Publication WO 97/07734, the disclosures of which are incorporated herein by reference, describe methods of using laser pulses to locally heat the stratum corneum to about 120xc2x0 C., thereby causing local ablation, in order to cause a single hole to develop in the stratum corneum through which large molecules may pass. Whereas some selectivity of ablation depth can be attained by varying the wavelength of the laser pulse, no feedback mechanism is disclosed whereby the laser pulses are terminated upon generation of the necessary damage to the stratum corneum.
PCT Publication WO 97/07734 also discloses thermal ablation of the stratum corneum using an electrically resistive element in contact with the stratum corneum, such that a high current through the element causes a general heating of tissue in its vicinity, most particularly the stratum corneum. As above, no means are disclosed to terminate current flow upon sufficient disruption of the stratum corneum. Additionally, thermal characteristics of skin vary highly across different areas of an individual""s skin, as well as among a group of subjects, making optimal thermal dosages, which produce the desired ablation without causing pain, very difficult to determine. Lastly, increasing transdermal molecular flow by increasing the permeability of the stratum corneum, whether using microneedles, laser energy, or resistive heating of tissue, is inherently a two step process: (a) position apparatus to generate holes, and (b) apply a patch to the skin, through which the molecules will flow.
Electroporation is also well known in the art as a method to increase pore size by application of an electric field. This process is described in an article by Chizmadzhev et al., entitled xe2x80x9cElectrical properties of skin at moderate voltages,xe2x80x9d Biophysics Journal, February, 1998, 74(2), pp. 843-856, which is incorporated herein by reference. Electroporation is disclosed as a means for transiently decreasing the electrical resistance of the stratum corneum and increasing the transdermal flux of small molecules by applying an electric field to increase the size of existing pores. Electroporation generally does not produce pores of sufficient diameter to pass large molecules therethrough. Additionally, optimal voltage profiles are difficult to determine because of naturally occurring variations as described hereinabove, as well as the lack of an accurate feedback mechanism to indicate achievement of the desired pore enlargement. If excessive voltage is applied, an irreversible breakdown occurs, resulting in damage to the skin and possible sensations of pain.
U.S. Pat. No. 5,019,034 to Weaver et al., whose disclosure is incorporated herein by reference, describes apparatus for applying high voltage, short duration electrical pulses on the skin to produce electroporation, and states that xe2x80x9c. . . reversible electrical breakdown . . . along with an enhanced tissue permeability, is the characteristic effect of electroporation.xe2x80x9d
It is an object of some aspects of the present invention to provide improved apparatus and methods for transdermal delivery of an active substance.
It is a further object of some aspects of the present invention to provide improved apparatus and methods for transdermal analyte extraction.
It is yet a further object of some aspects of the present invention to provide improved apparatus and methods for creating narrow channels through the stratum corneum of living skin by puncturing.
It is still a further object of some aspects of the present invention to provide improved apparatus and methods for reducing sensation and minimizing damage to skin underlying the stratum corneum during channel creation.
It is an additional object of some aspects of the present invention to provide improved apparatus and methods for controlling the timing of channel creation.
It is vet an additional object of some aspects of the present invention to provide improved apparatus and methods for regulating channel creation responsive to properties of the skin.
It is another object of some aspects of the present invention to provide improved apparatus and methods for puncturing the skin and/or transdermally delivering an active substance and/or transdermally extracting an analyte, using a miniature, self-contained device.
It is yet another object of some aspects of the present invention to provide improved apparatus and methods for transdermally delivering an active substance using a standard medical skin patch.
In preferred embodiments of the present invention, a device for enhancing transdermal movement of a substance comprises: (a) a skin patch, with at least two electrodes in contact with the skin of a subject; and (b) a control unit, coupled to the patch, which causes a current to pass between the electrodes through the stratum corneum epidermidis, in order to generate at least one micro-channel in the stratum corneum to enable or augment transdermal movement of the substance. Preferably, the control unit comprises switching circuitry to control the magnitude and/or duration of the electric field at the electrode.
The term xe2x80x9cmicro-channelxe2x80x9d as used in the context of the present patent application and in the claims refers to a pathway generally extending from the surface of the skin through all or a significant part of the stratum corneum, through which pathway molecules can diffuse. Preferably, micro-channels allow the diffusion therethrough of large molecules at a greater rate than the same molecules would diffuse through pores generated by electroporation. It is believed that such micro-channels are formed due to local power dissipation leading to ablation of the stratum corneum when an electric field of sufficient magnitude is applied to a small area of the skin, in contact with the electrodes, for a certain period of time. Unlike methods of electrically-promoted drug delivery known in the art, such as iontophoresis and electroporation, the present invention enables relatively large channels to be formed, through which even large molecules of the active substance can pass rapidly, without the necessity of ionizing or polarizing the molecules.
The current flow between the electrodes can be described as having two components: (a) a perpendicular component, which is generally perpendicular to the skin surface (and, if the associated electric field is sufficiently large, may cause current to go through the stratum corneum into the underlying epidermal tissue and dermis); and (b) a lateral component, generally parallel to the skin surface, which remains generally within the stratum corneum. Substantially all of the current generated at one electrode ultimately emerges from the skin and is taken up by an adjacent electrode.
In preferred embodiments of the present invention, methods and/or apparatus are employed to increase the relative value of the lateral component with respect to the perpendicular component. In general, the stratum corneum epidermidis (the superficial layer of the epidermis) demonstrates a significantly higher resistance to the passage of molecules therethrough than does the underlying epidermal tissue. It is therefore an object of these preferred embodiments of the present invention to form micro-channels in the stratum corneum by ablating the stratum corneum in order to increase conductance of the substance therethrough, and to generally not directly affect or damage epidermal tissue underlying the stratum corneum or in the innervated dermis. Additionally, limiting current flow substantially to the non-innervated stratum corneum is expected to decrease or eliminate the subject""s sensations, discomfort, or pain responsive to use of the present invention, particularly as compared with other procedures known in the art.
A voltage applied between two electrodes on the skin generates an electric field that is to a large extent confined to the volume in a vicinity of the electrodes. Thus, electrodes which are widely spaced produce a fieldxe2x80x94and current flow responsive theretoxe2x80x94which extends relatively deep into the skin. Conversely, electrodes which are closely spaced do not generate significant current flow at deeper layers. Therefore, in some preferred embodiments of the present invention, the electrodes of the device are separated by distances smaller than about 100 microns (but for some applications by distances of up to approximately 500 microns), in order to generate a current flow which is largely confined to a thin layer, comprising most or all of the stratum corneum. This effectively results in a desired larger value of the ratio of the lateral component to the perpendicular component, as described hereinabove.
In some of these preferred embodiments of the present invention, a high-frequency AC current with an optional DC current added thereto is applied between the closely-spaced electrodes in order to generate lateral capacitive currents in the stratum corneum and to cause breakdown and micro-channel formation in the stratum corneum.
In some preferred embodiments of the present invention, the patch comprises an array of electrodes, preferably closely-spaced electrodes, which act together to produce a high micro-channel density in an area of the skin under the patch. Preferably, the control unit and/or associated circuitry sequentially or simultaneously evaluates the current flow through each electrode, or a subset of the electrodes, in order to determine when one or more micro-channels have formed responsive to the applied field. Responsive thereto, the control unit discontinues application of the field. Since the formation of a micro-channel is typically marked by a local drop in electrical resistance of the skin, the control unit may, for example, reduce the voltage or current applied at any electrode wherein the current has exceeded a threshold. By reducing current flow upon or shortly after micro-channel formation, the likelihood of skin burns or pain sensations is minimized.
In some preferred embodiments of the present invention, a relatively high voltage is applied to the electrodes initially, so as to induce formation of micro-channels through the skin. A property of the current flow is detected, and the current is reduced or terminated when the property reaches a predetermined threshold. Preferably, the detected property of the current flow is secondary to changes in a conduction property of the skin, responsive to formation of one or more micro-channels through the stratum corneum.
Alternatively or additionally, a time-varying voltage V(t), characterized, for example, by the formula V(t)=VO+ktn, is applied between a first electrode and a second electrode in the skin patch until a shut-off signal is generated. (Constants k and n are nonnegative.) Other forms of V(t) may include a sinusoid, an exponential term, or a series of pulses. A current I(t), flowing responsive to the applied field, is measured by the control unit, as described hereinabove. Calculations of the values of ∫I(t)dt, dI/dt and/or d2I/dt2 are frequently performed. Comparisons of I and/or ∫I(t)dt and/or dI/dt and/or d2I/dt2 with respective threshold values are used as indicators of micro-channel formation and/or to determine when to generate the shut-off signal for the electrodes.
Further alternatively or additionally, in embodiments in which V(t) is sinusoidal, the control unit preferably calculates changes in a phase shift between V(t) and I(t) during application of the electric field, and controls the field responsive to these changes. It is believed that cells in the stratum corneum demonstrate capacitance, which causes the phase shift, and that ablation of the stratum corneum decreases the capacitance and is evidenced by a decrease in the phase shift.
Still further alternatively or additionally, the total charge which is passed through the skin is limited by a capacitor, inductor, or other energy-storage device. An appropriate choice of values for these components sets an absolute maximum quantity of charge which can pass through the skin, and thus limits any damage that can be caused thereby.
In some preferred embodiments of the present invention, one or more of the electrodes comprise or are coupled to an electrically conductive dissolving element, where the dissolving rate is generally proportional to the current passing through the electrode. When a sufficient quantity of charge has passed through the dissolving element, the electrode ceases to conduct electricity. Thus, a maximum total charge, Qtotal, is associated with an electrode, such that current flows through the element for only as long as q(t)=∫I(t)dt less than Qtotal. This serves as a safety feature, reducing the possibility of skin burns secondary to applied electric fields. Alternatively or additionally, the dissolving element is constructed so that it becomes non-conductive after a quantity of charge has passed therethrough which is sufficient to ablate the stratum corneum.
In some further preferred embodiments of the present invention, the electrodes are xe2x80x9cprintedxe2x80x9d directly on the skin, preferably by stamping or by employing a transfer patch of a conductive substance (such as, for example, a conductive ink containing silver grains). In applications of such embodiments of the present invention for transdermal drug delivery, the conductive substance preferably comprises a matrix holding the drug to be administered to a subject.
Preferably, the printed electrodes demonstrate a substantially complete loss of conductance therethrough upon ablation of the stratum corneum responsive to the applied electric field. Further preferably, each printed electrode comprises a material which is conductive only when current flowing therethrough remains below a threshold value. If the current exceeds the threshold, then thermal fusion of the material causes it to become largely nonconductive, i.e. the material acts as a fuse. Still further preferably, current continues to flow through the other electrodes until they reach the threshold current, at a time which is generally associated with the time required for ablation of the stratum corneum, as described hereinabove. In some of these embodiments, the control unit may be made substantially simpler than as described regarding other embodiments, and generally does not need other circuitry in order to determine whether to generate a shut-off signal.
In still further preferred embodiments of the present invention, two electrodes on the patch form a concentric electrode pair, in which an inner electrode generates a current which passes through the stratum corneum to an outer electrode surrounding the inner electrode. The distance between the inner and outer electrodes is preferably between about 50 and about 200 microns, or between 200 microns and about several millimeters, in order to maintain the ratio of the lateral to the perpendicular component of the current at a high value, as described hereinabove.
In some preferred embodiments of the present invention, a conductance-enhancing substance, preferably comprising a conductive cream or ink, is applied to the skin in order to increase the ratio of the lateral to the perpendicular component of current flow. Alternatively or additionally, the conductance-enhancing substance comprises a composition with a high diffusion coefficient, which diffuses into the lipid layers of the stratum corneum and further augments the selective power dissipation therein, in order to ablate the stratum corneum with substantially little damage to the underlying tissue. In some applications, the substance has an electrical charge associated therewith, such that when a small lateral field is applied, lateral diffusion of the substance within the stratum corneum is enhanced (i.e., iontophoresis of the substance).
In some of these preferred embodiments which utilize a conductance-enhancing substance, the substance further comprises an active substance, for example, a pharmaceutical product, dissolved or mixed therein. Since breakdown of the stratum corneum is often associated with removal of the enhanced conductivity path afforded by the conductance-enhancing substance, it is preferable in many of these embodiments to use a substantially constant voltage source to generate current at the electrodes. Removal of the enhanced conductivity path will result in a desired reduced power dissipation in the stratum corneum (P=V2/R), since the voltage remains constant while resistance increases.
In other preferred embodiments of the present invention, ablation of the stratum corneum is accomplished using a current-limited source to power the electrodes. It is believed that the stratum corneum generally displays high electrical resistance, while epidermal tissue underlying the stratum corneum has significantly lower electrical resistance. Ablation of the stratum corneum (i.e., removal of the high-resistance tissue) is therefore associated with a net decrease of electrical resistance between the electrodes, and the power dissipated in the epidermis following electrical breakdown will decrease, typically proportional to the change in resistance (P=I2R).
Monitoring changes in voltage, current, and/or phase for each electrode in the control unit may require, in certain implementations, a significant amount of circuitry. Therefore, in some preferred embodiments of the present invention, the control unit comprises one or more clusters of electrodes, in which monitoring and control are performed for each cluster rather than for the individual electrodes therein, The cluster is preferably over a relatively small area of skin, for example, from about 1 mm2 to about 100 mm2, in which properties of the skin are assumed to be substantially constant.
In some preferred embodiments of the present invention, the device is a stand-alone device, which enables transdermal delivery of an active substance or enhances transdermal motion of an analyte. Alternatively, the device creates micro-channels as described hereinabove and is then removed from the skin, in order to enhance the transdermal delivery of a substance into or out of a commercially-available skin patch subsequently placed on the skin. In other preferred embodiments of the present invention, the device is an add-on to commercially available transdermal drug delivery/analyte extraction devices, and serves primarily to create the micro-channels in the stratum corneum, and optionally to act as a vehicle through which the substance may pass.
In further preferred embodiments of the present invention, the device is integrated into a package approximately the size and shape of a credit card, upon the underside of which is disposed an electrode array and a drug delivery unit. The electrode array preferably comprises a plurality of linear electrode elements, each electrode element comprising a plurality of equally-spaced individual electrodes, connected in series. In a preferred embodiment, electrodes in adjacent linear electrode elements in the electrode array are separated by about 200 microns to about several millimeters. Preferably, spaces between the electrodes in the electrode array form the drug delivery unit, and are used to store a drug which is actively or passively delivered to the skin following the ablation thereof. Further preferably, a cover on the underside of the card is removed prior to use, in order to expose the electrodes, the drug, and an adhesive which secures the card to the subject""s skin.
In some preferred embodiments of the present invention, the device enables transdermal delivery of an active substance in conjunction with analyte extraction and analysis of the analyte. In a preferred embodiment, the device delivers an active substance through the skin of the subject, and subsequently extracts an analyte through the skin to facilitate the determination of the level of a relevant biological substance. In another preferred embodiment, the device first extracts an analyte through the subject""s skin, then performs an analysis of the analyte, and subsequently determines an appropriate dose of an active substance to deliver to the subject. Alternatively or additionally, the extraction and analysis of the analyte are performed to determine which of a plurality of active substances to deliver to the subject.
In accordance with a further preferred embodiment of the present invention, the device comprises a sensor, which detects other physiological parameters of the subject, such as, but not limited to, blood pressure, temperature, heart rate, and respiration rate. Preferably, these parameters are analyzed to assist in the determination of the type or quantity of active substance to be delivered to the subject. Further preferably, the analysis of the physiological parameters is used to determine the timing of the delivery of the active substance.
In a preferred embodiment of the present invention, the device comprises a body fluid analysis unit, into which the subject deposits, for example, a sample of blood, urine, or saliva. Preferably, the body fluid analysis unit is included on the card with the electrodes and drug delivery unit, allowing results of analysis of the body fluid to be used in determining parameters of the treatment performed by the device. For example, the current level supplied to the electrodes, the type and amount of drug to be delivered to the subject, or the scheduling of drug delivery may be determined responsive to results of the body fluid analysis.
For some applications, the device comprises a pressure generation unit that is used to propel the active substance onto ablated regions of skin. Typically, an electric current passed through a liquid stored in the device generates a gas which creates a desired amount of pressure to facilitate the transfer of active substance into the skin.
Alternatively or additionally, the device comprises a transport facilitation unit comprising an ultrasonic transducer which increases the transport of the active substance into the skin, e.g., by imparting high energy to molecules of the active substance and/or by enhancing conductance of the skin to the substance. Further alternatively or additionally, iontophoresis or other methods known in the art are employed to improve the transfer of the active substance into the skin of the subject, the transfer being initially facilitated by ablation of the stratum corneum.
In a preferred embodiment of the present invention, the device comprises a timing unit, which allows the active substance to be delivered to the skin on a specified schedule, e.g., three times a day. Alternatively or additionally, ablation of the skin is initiated in accordance with a schedule set by the timing unit and another factor, such as eating or sleeping. Further alternatively or additionally, the timing unit initiates analyte extraction and analysis on a specified schedule, such that the active substance is delivered to the skin as necessary. For example, blood sugar could be tested every hour, and insulin delivered to the subject responsive to the blood sugar level. For some applications, particularly to facilitate a diagnosis, the timing unit is configured to initiate analyte extraction and analysis at a specified time after the active substance has been delivered to the skin. This allows the active substance the prescribed time to enter the subject and produce a desired effect before testing occurs.
Preferably, the device comprises an output unit to communicate relevant information to the subject. For example, the subject may be informed regarding the status of the device, the outcome of analyte analysis, and the amount of active substance delivered to the subject. Preferably, the output unit comprises a speaker, to give an audible output, and/or a display, such as an LCD, to present visual information to the subject.
In a preferred embodiment of the present invention, the device comprises an infrared or other wireless or wired data port for transferring data to or receiving instructions from another computer. For example, transmitted data may be designated for storage in a local computer or for analysis by a computer or physician at a remote healthcare facility. In a preferred application, the data port transmits the amount and timing of drug delivered to the subject, and/or results of analyte or body fluid analysis. Typically, the data port is configured to transmit the data to a local computational device, such as a computer, a personal digital assistant (PDA) or a cellular telephone, from which the data can subsequently be accessed by a health care professional at a remote site. Preferably, the health care professional is enabled to respond to the received information by sending instructions back to the device, such that the device changes one or more operational parameters thereof responsive to the instructions.
There is therefore provided, in accordance with a preferred embodiment of the present invention, a device for delivering a substance to skin of a subject, including:
a substance storage unit, which is adapted to store the substance;
a sensor, which is adapted to generate a sensor signal responsive to a physiological parameter of the subject;
one or more electrodes, which are adapted to be placed at respective sites on the skin; and
a substance delivery unit, which is adapted to receive the signal, and, responsive thereto, to drive at least some of the one or more electrodes to apply to respective ones of the sites on the skin a current capable of ablating stratum corneum epidermidis of the skin, so as to facilitate delivery of the substance from the storage unit through the skin at the respective ones of the sites.
Preferably, the sensor includes an analysis unit, which is adapted to receive a portion of a body fluid of the subject, to analyze the portion, and to generate the sensor signal responsive to the analysis of the portion. Alternatively or additionally, the analysis unit is adapted to drive at least one of the one or more electrodes to apply a substantially DC current to the skin so as to enhance by means of iontophoresis extraction through the skin of the portion of the body fluid. Still further alternatively or additionally, the analysis unit is adapted to analyze the portion of the body fluid to determine a level of sugar in blood of the subject, and to generate the signal responsive thereto. For example, the substance storage unit may be adapted to store insulin.
In a preferred embodiment, the substance delivery unit is adapted:
to designate at a first time a first number of the one or more electrodes to drive to apply the current, responsive to a desired rate of delivery of the substance during a first time period, and
to designate at a second time a second number of the one or more electrodes to drive to apply the current, responsive to a desired rate of delivery of the substance during a second time period, the second number being different from the first number.
Alternatively or additionally, the substance delivery unit is adapted to:
drive a first subset of the one or more electrodes to apply during a first time period, a current capable of ablating stratum corneum in a vicinity of the first subset of the one or more electrodes, and
drive a second subset of the one or more electrodes to apply, during a second time period, a current capable of ablating stratum corneum in a vicinity of the second subset,
wherein the second subset includes at least one electrode which is not in the first subset.
Still further alternatively or additionally, the substance delivery unit is adapted to drive a subset of the one or more electrodes to apply:
during a first time period, a current capable of ablating stratum corneum in a vicinity of the subset of the one or more electrodes, and
during a second time period, a current capable of ablating stratum corneum in the vicinity.
In a preferred embodiment, the sensor is adapted to measure a property of skin in the vicinity.
For some applications, at least one of the one or more electrodes is adapted to apply to the skin a substantially DC current capable of enhancing by means of iontophoresis the passage of a material through the skin. For example, the substance delivery unit may be adapted to drive the at least one of the one or more electrodes to apply the substantially DC current to the skin so as to enhance by means of iontophoresis the delivery of the substance through the skin.
Preferably, the device includes a transport facilitation unit, adapted to facilitate transport of a material through the skin.
In a preferred embodiment, the device includes a communications unit, which is adapted to receive the signal and, responsive thereto, to transmit information to a computer external to the device. Alternatively or additionally, the device includes a communications unit, which is adapted to receive an instruction from a remote computer, and wherein the substance delivery unit is adapted to modify, responsive to the instruction, a parameter of the current.
In a preferred embodiment, the sensor includes an analysis unit which is adapted to drive a subset of the one or more electrodes to apply a current to the skin, so as to facilitate extraction therefrom of an analyte in a body fluid of the subject. For example, the analysis unit may be adapted to drive the subset of the one or more electrodes to apply a current to the skin capable of ablating stratum corneum epidermidis of the skin.
For some applications, the sensor includes an analysis unit which is adapted to analyze at least one of; blood of the subject, urine of the subject, and saliva of the subject, and to generate the signal responsive thereto.
There is further provided, in accordance with a preferred embodiment of the present invention, a device for delivering a substance to skin of a subject, including:
a housing;
a set of electrodes, fixed to the housing, which set of electrodes is adapted to be placed at respective sites on the skin;
an analysis unit, fixed to the housing, which analysis unit is adapted to drive a first subset of the set of electrodes to apply a current to the skin so as to facilitate extraction therefrom of an analyte, to analyze the analyte, and to generate a signal responsive to the analysis of the analyte;
a substance storage unit, fixed to the housing, which storage unit is adapted to store the substance; and
a substance delivery unit, fixed to the housing, which delivery unit is adapted to receive the signal, and, responsive thereto, to drive a second subset of the set of electrodes to apply current to the skin so as to facilitate delivery of the substance from the storage unit through the skin.
In a preferred embodiment, the device includes a transport facilitation unit, adapted to facilitate transport of a material through the skin.
In a preferred embodiment, the analysis unit is adapted to drive the first subset of the set of electrodes to apply a substantially DC current to the skin, to enhance by means of iontophoresis the extraction of the analyte through the skin. Alternatively or additionally, the substance delivery unit is adapted to drive the second subset of the set of electrodes to apply a substantially DC current to the skin to enhance by means of iontophoresis the delivery of the substance through the skin.
For some applications, the first subset of electrodes includes at least one electrode in the second subset of electrodes. For other applications, the first subset of electrodes consists exclusively of electrodes which are not in the second subset of electrodes.
There is yet further provided, in accordance with a preferred embodiment of the present invention, a device for analyzing an analyte extracted through skin of a subject, including:
one or more electrodes, which are adapted to be placed at respective sites on the skin;
a control unit, which is adapted to drive the one or more electrodes to apply a current to the respective sites on the skin capable of ablating stratum corneum epidermidis of the skin, so as to facilitate extraction of the analyte through the skin;
an analysis unit, which is adapted to analyze the analyte and to generate a signal responsive to the analysis of the analyte; and
a communications unit, which is adapted to receive the signal and, responsive thereto, to transmit information to a computer external to the device.
There is still further provided, in accordance with a preferred embodiment of the present invention, a device for regulating a substance in the body of a subject, including:
an analysis unit, which is adapted to receive a portion of a body fluid of the subject, to analyze the portion, and to generate a signal, responsive to an actual level of the substance in the portion;
a material storage unit, which is adapted to store two or more different material in respective regions of the material storage unit;
one or more electrodes, which are adapted to be placed at respective sites on the skin; and
a material delivery unit, which is adapted to receive the signal, and, responsive thereto, to drive the one or more electrodes to apply current to the respective sites on the skin capable of facilitating delivery of one or more of the materials from the storage unit through the skin at the respective sites, so as to maintain a desired level of the substance in the body of the subject.
For some applications, the device includes a transport facilitation unit, adapted to facilitate transport of the portion through the skin. Alternatively or additionally, the device includes a transport facilitation unit, adapted to facilitate transport of one of the substances through the skin.
Preferably, the material delivery unit is adapted to configure the current, responsive to the signal, so as to facilitate delivery of the material stored in one of the regions, while substantially not facilitating the delivery of the material stored in another one of the regions.
There is also provided, in accordance with a preferred embodiment of the present invention, a device for analyzing an analyte extracted through skin of a subject, including:
a housing;
one or more electrodes, fixed to the housing, which one or more electrodes are adapted to be placed at respective sites on the skin;
a control unit, fixed to the housing, which control unit is adapted to drive at least some of the one or more electrodes to apply a current to the respective sites on the skin capable of ablating stratum corneum epidermidis of the skin, so as to facilitate extraction of the analyte through the skin; and
an analysis unit, fixed to the housing, which is adapted to analyze the analyte and to generate a signal responsive to the analysis of the analyte.
For some applications, the control unit is adapted:
to designate at a first time a first number of the one or more electrodes to drive to apply the current, responsive to a desired extraction rate of the analyte during a first time period, and
to designate at a second time a second number of the one or more electrodes to drive to apply the current, responsive to a desired extraction rate of the analyte during a second time period, the second number being different from the first number.
In a preferred embodiment, the control unit is adapted to:
drive a first subset of the one or more electrodes to apply, during a first time period, a current capable of ablating stratum corneum in a vicinity of the first subset of the one or more electrodes, and
drive a second subset of the one or more electrodes to apply, during a second time period, a current capable of ablating stratum corneum in a vicinity of the second subset,
wherein the second subset includes at least one electrode which is not in the first subset.
Preferably, the device includes a sensor, adapted to measure a physiological parameter of the subject and to generate a sensor signal responsive thereto, wherein the control unit is adapted to designate the first and second times responsive to the sensor signal.
For some applications, the control unit is adapted to drive a subset of the one or more electrodes to apply:
during a first time period, a current capable of ablating stratum corneum in a vicinity of the subset of the one or more electrodes, and
during a second time period, a current capable of ablating stratum corneum in the vicinity.
In a preferred embodiment, the device includes a sensor, adapted to measure a physiological parameter of the subject and to generate a sensor signal responsive thereto, wherein the control unit is adapted to drive the at least some of the one or more electrodes to apply the current responsive to the sensor signal. For example, the sensor may be adapted to measure a physiological parameter selected from the list consisting of: transepidermal water loss (TEWL), a property of the skin, temperature, blood pressure, heart rate, and respiration rate.
Typically, the device includes:
a substance storage unit, which is adapted to store a substance; and
a substance delivery unit, which is adapted to receive the signal generated by the analysis unit, and, responsive thereto, to drive a subset of the one or more electrodes to apply a substance-delivery-unit current to respective ones of the sites on the skin so as to facilitate delivery of the substance from the storage unit through the skin at the respective ones of the sites.
There is additionally provided, in accordance with a preferred embodiment of the present invention, a method for delivering a substance to skin of a subject, including:
sensing a physiological parameter of the subject;
analyzing the parameter; and
responsive to the analysis of the parameter, applying to the skin a current capable of ablating stratum corneum epidermidis of the skin, so as to facilitate delivery of the substance into the skin.
There is yet additionally provided, in accordance with a preferred embodiment of the present invention, a method for analyzing an analyte extracted through skin of a subject, including:
applying to the skin a current capable of ablating stratum corneum epidermidis of the skin, so as to facilitate extraction of the analyte through the skin;
analyzing the analyte in a device that is attached by the subject to the skin; and
responsive to the analysis, transmitting information to a computer external to the device.
There is still additionally provided, in accordance with a preferred embodiment of the present invention, a method for regulating a substance in the body of a subject, including:
storing two or more different materials in respective regions of a material storage unit;
sensing a physiological parameter of the subject;
analyzing the parameter to obtain an indication of an actual level of the substance in the body of the subject;
selecting a material from the two or more materials, responsive to the analysis; and
applying to skin of the subject a current capable of facilitating delivery of the selected material from the storage unit into the skin, so as to maintain a desired level of the substance in the body of the subject.
There is also provided, in accordance with a preferred embodiment of the present invention, a device for facilitating transdermal passage of a substance through skin of a subject, including:
one or more electrodes, which are adapted to be placed at respective sites on the skin;
a control unit, which is adapted to drive at least some of the one or more electrodes to apply to respective ones of the sites on the skin a current capable of ablating stratum corneum epidermidis of the skin; and
a transport facilitation unit, adapted to facilitate transdermal passage of the substance through an ablated region of the stratum corneum.
For some applications, the transport facilitation unit includes a pressure generation unit, which is adapted to generate a pressure in a vicinity of the skin capable of facilitating the transport of the substance through the skin. In a preferred embodiment, the device includes a storage unit, adapted to store the substance, and the pressure generation unit is adapted to generate a positive pressure capable of facilitating the delivery of the substance from the storage unit through the skin. Alternatively or additionally, the pressure generation unit is adapted to generate a negative pressure capable of facilitating extraction of the substance through the skin.
For further applications, the transport facilitation unit includes a mechanical vibration unit, which is adapted to generate vibrations in the skin capable of facilitating the transport of the substance through the skin. In a preferred embodiment, the device includes a storage unit, adapted to store the substance, and the mechanical vibration unit is adapted to generate vibrations capable of facilitating delivery of the substance from the storage unit through the skin. Alternatively or additionally, the mechanical vibration unit is adapted to generate vibrations capable of facilitating extraction of the substance through the skin.
For yet further applications, the transport facilitation unit includes an ultrasound generation unit, which is adapted to generate ultrasound waves in a vicinity of the skin capable of facilitating transport of the substance through the skin. In a preferred embodiment, the device includes a storage unit, adapted to store the substance, and the ultrasound generation unit is adapted to generate the ultrasound waves so as to facilitate delivery of the substance from the storage unit through the skin. Alternatively or additionally, the ultrasound generation unit is adapted to generate the ultrasound waves so as to facilitate extraction of the portion of the body fluid through the skin.
There is further provided, in accordance with a preferred embodiment of the present invention, a device for facilitating transdermal passage of a substance through skin of a subject, including:
one or more electrodes, which are adapted to be placed at respective sites on the skin; and
a control unit, which is adapted:
to drive at least some of the one or more electrodes to apply to respective ones of the sites on the skin a current capable of ablating stratum corneum epidermidis of the skin, so as to facilitate transdermal passage of the substance through the skin,
to designate at a first time a first number of the one or more electrodes to drive to apply the current, responsive to a desired rate of passage of the substance during a first time period, and
to designate at a second time a second number of the one or more electrodes to drive to apply the current, responsive to a desired rate of passage of the substance during a second time period, the second number being different from the first number.
Preferably, the control unit is adapted to drive the current as an alternating current (AC), e.g., having a frequency of the current to be between about 1 kHz and about 300 kHz.
Typically, the control unit is adapted to drive the current that is capable of causing ablation during a first time period, so as to facilitate passage of the substance through an ablated area of the stratum corneum during a second time period, subsequent to the first time period.
There is yet further provided, in accordance with a preferred embodiment of the present invention, a device for facilitating transdermal passage of a substance through skin of a subject, including:
one or more electrodes, which are adapted to be placed at respective sites on the skin; and
a control unit, which is adapted:
to drive a first subset of the one or more electrodes to apply during a first time period, a current capable of ablating stratum corneum in a vicinity of the first subset of the one or more electrodes, so as to facilitate transdermal passage of the substance through the skin, and
to drive a second subset of the one or more electrodes to apply, during a second time period, a current capable of ablating stratum corneum in a vicinity of the second subset, so as to facilitate transdermal passage of the substance through the skin,
wherein the second subset includes at least one electrode which is not in the first subset.
In a preferred embodiment, the control unit is adapted to drive the current that is capable of causing ablation during the first time period, so as to facilitate passage of the substance through an ablated area of the stratum corneum during a substance-passage time period subsequent to the first time period.
There is still further provided, in accordance with a preferred embodiment of the present invention, a device for facilitating transdermal passage of a substance through skin of a subject, including:
one or more electrodes, which are adapted to be placed at respective sites on the skin; and
a control unit, which is adapted to drive a subset of the one or more electrodes to apply:
during a first time period, a current capable of ablating stratum corneum in a vicinity of the subset of the one or more electrodes, and
during a second time period, a current capable of ablating stratum corneum in the vicinity of the subset of the one or more electrodes.
The present invention will be more fully understood from the following detailed description of the preferred embodiments thereof, taken together with the drawings in which: